Sepsis is the leading cause of death in most intensive care units with over 210,000 people succumbing to overwhelming infection (or the resultant multiple organ failure) in the United States annually. A recent epidemiologic study estimated that 750,000 people develop sepsis annually at a cost of $16.7 billion dollars. Studies show that apoptosis is an important mechanism of cell death in sepsis and that prevention of apoptosis can improve survival in animal models of sepsis. Apoptosis can proceed by either a receptor or mitochondrial mediated pathway. In certain types of cells subjected to particular apoptotic stimuli, the two pathways can be linked such that both pathways are operative in the same cell. Understanding the mechanisms of apoptotic cell death in sepsis is vital because this knowledge may reveal the inciting stimuli and enable an effective therapy aimed at the responsible pathway. Currently, the particular apoptotic pathway operative in sepsis, i.e., receptor versus mitochondrial, is debated and both pathways have been reported to be activated. Preliminary findings in our laboratory indicate that both pathways may be operative in sepsis-induced lymphocyte apoptosis although they appear to be occurring in anatomically different regions of the spleen, consistent with effects on different lymphocyte phenotypes. Like Bcl-2, the serine threonine kinase Akt is an oncoprotein which prevents cell death due to a variety of apoptotic stimuli. The exact mechanism of action of Akt is unknown but in some instances it appears to work by a mechanism that is distinct from that of Bcl-2. Preliminary findings in our laboratory show that lymphocytes from mice that over express Akt in T cells do not undergo sepsis-induced apoptosis and the mice have improved survival compared to non-transgenic. The guiding hypotheses of this proposal are: I) lymphocyte apoptosis in sepsis proceeds via both receptor and mitochondrial mediated pathways and, ii) over-expression of Akt in T cells will prevent lymphocyte apoptosis and improve sepsis survival. Studies will be conducted using a clinically relevant animal model of sepsis. In addition, translational studies will be conducted in blood from critically ill patients with and without sepsis. Note that preliminary findings demonstrate increased lymphocyte apoptosis in patients with sepsis versus critically ill non-septic patients. This proposal will provide important new information regarding mechanisms of apoptotic lymphocyte death in sepsis and may ultimately lead to a more effective therapy for this highly lethal disorder.